The signaling pathways regulating differentiation of the exocrine pancreas during embryonic development are poorly understood. These pathways may play a critical role in several human disease states, including chronic pancreatitis and pancreatic ductal adenocarcinoma. The long term goal of this research project is to identify molecular pathways responsible for controlling precursor cells in exocrine pancreas. Preliminary studies suggest that changes in acinar cell differentiation may be regulated by novel interactions between the EGF and Notch signaling pathways. Specifically, it has been demonstrated that TGF-alpha alters the differentiation status of acinar cells in mouse pancreas, reactivating a developmental program characterized by expansion of embryonic-like epithelium. The effects of TGF-alpha on exocrine differentiation appear to be mediated by activation of Notch signaling pathways, as evidenced by transactivation of Notch target genes and the ability of activated Notch-1 to induce similar effects. Moreover, selective inactivation of the Notch partner RBP-J-kappa in exocrine precursor cells results in pancreatic hypoplasia and a failure to generate mature acinar and ductal cell types. Based on these findings, we propose that Notch signaling is iteratively utilized to regulate normal development of the exocrine pancreas, and that abnormal Notch activation may be responsible for generating developmental plasticity and epithelial proliferation in the adult gland. To test this hypothesis, the following Specific Aims will be pursued: First, to investigate the role of Notch signaling in acinar cell differentiation during normal pancreatic development. Second, to examine the role of Notch signaling during transdifferentiation events in adult pancreas. Finally, to determine the effects of lineage-specific manipulation of Notch signaling in mouse exocrine pancreas, utilizing both transgenic and Cre/lox-based approaches. To accomplish these studies, the investigators have established a multidisciplinary team of scientists with noted expertise in the fields of pancreatic cell biology, Notch signaling, and mouse gene targeting. It is anticipated that these studies will provide important new insights regarding regulation of exocrine pancreatic precursor cells, and potentially generate new therapeutic strategies for diseases of the exocrine pancreas.